A fundamental goal in neuroscience is to understand mechanisms underlying the ability to create memories from sensory experience. While large structures such as the hippocampus are known to be critical for certain types of learning, memories are ultimately thought to be represented in sparsely distributed neuronal ensembles within these larger structures. Currently, there are no tools that allow for the identification and manipulation of these ensembles, which has limited our understanding of the molecular and cellular processes underlying learning and memory. We have previously reported that the activity regulated transcription factor Npas4 is selectively induced in a sparse population of CA3 hippocampal neurons by contextual learning. Furthermore, expression of Npas4 in the hippocampus is necessary for contextual memory formation. The goal of this research proposal is to determine if neurons expressing Npas4 following contextual learning comprise a memory circuit in CA3. Using a genetic reporter that is activated by Npas4, we will manipulate the electrical and biochemical properties of neurons expressing Npas4 following contextual learning, in order to test whether this population represents a neuronal ensemble required for information processing and memory recall. These experiments will provide unprecedented access to an active neuronal ensemble, which may lead to a greater understanding of the mechanisms underlying learning and memory. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to examine the mechanism of memory formation. The vast majority of neurological orders lead to profound impairments in learning and memory. By understanding the basic mechanisms of memory formation we can begin to develop therapeutic strategies to reverse these impairments.